Tamoxifen, one of the triphenylethylene compounds, is the Z-isomer of 1,2-diphenyl-1-[4-(2-N,N-dimethylamino)ethoxy]phenyl-1-butene as shown by the following formula. ##STR2##
Concerning the synthesis of tamoxifen or the corresponding E-isomer, many methods have been reported (e.g., Journal of the Chemical Society Perkin Transactions I, (3), 475 (1986) and Synthetic Communications, 17 (10), 1247 (1987)). In these well-known methods, however, the corresponding E-isomer and Z-isomer are formed as a mixture. Of the two isomers, only the Z-isomer has the desired biological activities and therefore the Z-isomer must be separated by fractional crystallization, chromatography or the like.
In the synthesis of 1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-[4-(2-N,N-dimethylamino)ethoxy ]phenyl-1-butene as well, a mixture of the E-isomer and the Z-isomer is formed. However, of the E-isomer and the Z-isomer of the end products which are derived from these compounds, only the Z-isomer has the desired biological activities. Therefore, Z-isomer needs to be separated from the mixture by means of fractional crystallization, chromatography or the like, as in the preparation of tamoxifen. Another problem is a high cost of producing the Z-isomer because only a limited amount of the Z-isomer is collected.
Also a method is reported wherein a mixture of a hydrochloric acid salt of tamoxifen and a hydrochloric acid salt of its E-isomer is heated in a concentrated hydrochloric acid for many hours to thereby convert the hydrochloric acid salt of the E-isomer to a hydrochloric acid salt of tamoxifen (Japanese Examined Patent Publication (Kokoku) No. 75224/1992). However, when the inventors of the present invention employed this technique in an attempt to convert 1-(4-hydroxyphenyl)-2-(4-isopropylphenyl)-1-[4-(2-N,N-dimethylamino)ethoxy ]phenyl-1-butene or the like under the same condition, the application of this technique proved to be unsuccessful because the rate of decomposition was faster than the rate of conversion. This technique further has a problem of increased cost because safety should be assured against a large excess amount, i.e., 20 equivalents or more, of the strong acid used with heating and the conversion takes a long period of time of at least 8 hours.